Neurons can be infected by viruses, potentially leading to propagation and spread of the virus within the central nervous system, cell death and encephalitis. Unlike peripheral cells which may be infected with viruses, the immune system has developed cell-sparing mechanisms of eliminating virus growth. These studies are directed at understanding host cytokine responses which regulate the replication of virus in neurons. In this competing renewal, Aims 1 and 2 are focused on the sensitization of neurons by type 1 interferon (IFN-beta). We will determine the cellular pathways which are activated and are able to effect an inhibitory role on the viral life cycle of vesicular stomatitis virus (VSV); preliminary data show that these are distinct from that used by IFN-gamma. In most cell types, RNA viruses readily induce the production of IFN-beta during their replication, which includes double stranded RNA intermediates. However, in our preliminary studies, VSV is an exception, and no IFN-beta was detected during infection both in vivo and in vitro. We will characterize the means by which VSV prevents neuronal synthesis of IFN-beta which could protect neighboring cells. We will determine the mechanism of peripheral induction of IFN-beta gene expression at 24h post intranasal infection, and examine the role of Toll Like Receptors (TLR) in the responses both of neurons and of splenocytes; we will determine if PDC are responsible for IFN-beta synthesis. Aim 3 will continue our studies on the antiviral effector which is induced by type 2 IFN (IFN-gamma) nitric oxide (NO); we have shown that mRNA for NOS-1, the neuronal isoform of nitric oxide synthase, does not change in cells treated with IFN-gamma, but the amount of the enzyme increases as does its activity. Studies are designed to define the novel mechanism of the increase in the enzyme which is induced by treatment of neurons with IFN-gamma. In aim 4, we will elucidate the mechanism by which this small molecule, NO, is able to inhibit viral protein synthesis and release of infectious virions from neurons. These studies are important because the insights gained will be beneficial in developing new and novel treatments for viral encephalitis considered new and emerging infections. They elucidate previously unsuspected interactions between the immune system and the central nervous system.